The goal of this project is to better understand the impact of mechanical and biologic factors on the progression of tibiofemoral osteoarthritis (OA). This project builds on the observations that in vivo dynamic loading and biologic factors can result in destabilization of the normal coupling of degradation and synthesis of articular cartilage, and that the pattern of these events is likely to contribute to the substantial variation in patient outcome. Hypothesis: The rate of progression of medial compartment tibiofemoral OA is correlated with dynamic loading during gait, (e.g., adduction moment at knee), as well as with high serum levels of HA and COMP and low serum levels of markers of matrix synthesis and repair [epitope 846 and CII propeptide of collagen type II (CPII)]. Those with the highest rates of progression will have dynamic loads coupled with alterations in these serum markers. 140 patients with medial compartment knee OA will be enrolled. Gait measurements will be obtained at 18 and 36 months. Serum levels of HA, COMP, epitope 846 and CPII will be obtained at 0, 18 and 36 months. Potentially confounding variables including age, body mass index, pain, alignment, and laxity will also be measured. Radiographic progression (changes in narrowest medial compartment interbone distance and other radiographic outcomes, from a weight-bearing, semi-flexed view) and functional status progression will be assessed using baseline, 18 and 36 month data, Generalized estimating equations and multiple regression statistical methods will be used. The contribution of the dynamic loading and of the serum level of each marker, as ell as the changes in these factors, to changes in specific outcome variables will be analyzed, while adjusting for appropriate confounders. A developmental project will also be conducted to measure bone density distribution in the proximal tibia on a subset of patients enrolled in this study. Bone distribution measures will be correlated with the load, markers and outcome measures. The importance and clinical significance of understanding the factors influencing the variable rate of progression of knee OA has been recognized and supported in a Multipurpose Arthritis and Musculoskeletal Disease Center Education, Epidemiology, and Health Services Research project (the MAMDC study) at Northwestern University (NU). The proposed study will take advantage of outcome and covariate data from that study.